Long-term efficacy and safety of zolpidem extended-release 12.5 mg, administered 3 to 7 nights per week for 24 weeks, in patients with chronic primary insomnia: a 6-month, randomized, double-blind, placebo-controlled, parallel-group, multicenter study

Abstract

Study objectives: To evaluate long-term efficacy and safety of zolpidem extended-release 3 to 7 nights/week for chronic primary insomnia.

Design: Multicenter, 25-week, phase IIIb, randomized, double-blind, placebo-controlled, parallel-group.

Setting: Outpatient; visits every 4 weeks.

Patients: Aged 18 to 64 years; DSM-IV criteria for chronic primary insomnia; > or =3 months of difficulty initiating or maintaining sleep or experiencing nonrestorative sleep.

Interventions: Single-dose zolpidem extended-release 12.5 mg (n = 669) or placebo (n = 349), self-administered from a minimum of 3 nights/week to a maximum of 7 nights/week.

Measurements and results: Patient's Global Impression (PGI) and Clinical Global Impression-Improvement (CGI-I) were assessed every 4 weeks up to week 24. Patient Morning Questionnaire (PMQ), recorded daily, assessed subjective sleep measures-sleep onset latency (SOL), total sleep time (TST), number of awakenings (NAW), wake time after sleep onset (WASO), and quality of sleep (QOS)-and next-day functioning. At week 12, PGI, Item 1 (aid to sleep), the primary endpoint, was scored as favorable (i.e., "helped me sleep") by 89.8% of zolpidem patients vs. 51.4% of placebo patients (P < 0.0001, based on rank score) and at week 24 by 92.3% of zolpidem extended-release patients vs. 59.7% of placebo patients. Zolpidem extended-release also was statistically significantly superior to placebo at every time point for PGI (Items 1-4) and CGI-I (P < 0.0001, rank score), TST, WASO, QOS (P < 0.0001), and SOL (P < or = 0.0014); NAW (Months 2-6; P < 0.0001). Sustained improvement (P < 0.0001, all time points) was observed in morning sleepiness and ability to concentrate (P = 0.0014, month 6) with zolpidem extended-release compared with placebo. Most frequent adverse events for zolpidem extended-release were headache, anxiety and somnolence. No rebound effect was observed during the first 3 nights of discontinuation.

Conclusions: These findings establish the efficacy of 3 to 7 nights per week dosing of zolpidem extended-release 12.5 mg for up to 6 months. Treatment provided sustained and significant improvements in sleep onset and maintenance and also improved next-day concentration and morning sleepiness.

Figure 1

Study design.

Figure 2

Summary of inclusion disposition: screened population.

Figure 3

Improvements in PGI scores for Items 1, 2, 3, and 4 over 6 months of treatment. Scores in the zolpidem extended-release group were higher than those in the placebo group at all 4-week intervals. Improvements in the zolpidem extended-release group were significantly superior at all time points (P < 0.001) based on rank scores for PGI Items 1, 2, and 3 (data not shown) and the percentages displayed for PGI Item 4 (chi square test). PGI = Patient's Global Impression.

Figure 4

Improvements in CGI scores (“much improved” or “very much improved”) over 6 months of treatment. Based on rank scores (data not shown), the improvement in insomnia symptoms was significantly greater in the zolpidem extended-release group than in the placebo group at all 4-week intervals of the 24-week treatment period (P < 0.001). CGI = Clinical Global Impression.

Figure 5

Change from baseline in PMQ over 6 months of treatment. For each of the 6 treatment months, patients who received zolpidem extended-release reported significantly greater improvement in TST (P < 0.0001), WASO (P < 0.0001), and SOL (P ≤ 0.0014) than did patients who received placebo. Improvement in NAW was also significantly greater at months 2 to 6 in the zolpidem extended-release patients (P < 0.0001). NAW = number of nocturnal awakenings; SOL = sleep onset latency; TST = total sleep time; WASO = wake after sleep onset.

Figure 6

Improvements from baseline in PMQ scores for ability to concentrate and morning sleepiness. For each of the 6 months of treatment, patients who received zolpidem extended-release reported significantly greater improvement than did patients who received placebo in the ability to concentrate (months 1 to 5, P < 0.0001; month 6, P = 0.0014) and in morning sleepiness (months 1 to 6, P < 0.0001).